The proposed research will investigate the human and HHV8 homologs of a newly discovered T cell costimulatory pathway defined by the OX-2 protein. Recent experiments have supported the hypothesis that T cell costimulatory signals represent an important physiologic and therapeutic control point for T cell mediated immune responses. Since T cell homeostasis is central to diverse immunologic mechanisms spanning autoimmunity, tumor biology and transplantation, their study is medically relevant. One extensively studied costimulatory pathway, the B7/CD28 pathway, delivers its signal when a receptor on T cells, called CD28, is engaged by either of two ligands, B7-1 or B7-2, expressed on antigen presenting cells. A literature search for additional B7-like proteins identified OX-2, a rat lymphocyte activation marker, as a promising candidate gene. Despite the failure of OX-2 to bind the B7 receptors, CD28 and CTLA4, it can stimulate T cell proliferation. In addition, this proliferation occurs in the apparent absence of IL-2, IL-4 or IF-gamma. Further interest in OX-2 has recently emerged from the finding that human herpes virus 8 (HHV8) as well as other herpes viruses encode OX-2 homologs. HHV8 is the causative agent for Kaposi's sarcoma, and has been primary effusion lymphoma. Other herpes virus encoded genes with homology to mammalian genes have been documented to modulate lymphocyte migration and antigen presentation. A viral OX-2 homolog therefore suggests that OX-2 plays a role in T cell function relevant to the viral pathogenesis. Taken together, these data indicate that OX-2 acts through a non-B7/CD28 pathway leading to functionally distinct consequences. We have recently generated mAbs to murine OX-2 which we intend to use as probes to assess the functional contribution of OX-2 to antigen presentation in skin resident, professional APCs. These reagents will also permit us to take advantage of a variety of knockout mouse models (i.e. CD28 -/-). The absence of costimulation through the predominant B7/CD28 pathway in the CD28 deficient mice will allow us to assess the role of this additional costimulatory pathway and the specialized niches in which it may function. These novel mouse specific reagents will allow us to measure levels of expression in the skin following a variety of stimuli and to determine to what extent this pathway is functions, by measuring DTH responses in vivo and to correlate this with APC function in vitro.